The goal of this proposal is to identify and characterize susceptibility loci for common colorectal cancer. In order to accomplish this task we will: 1) ascertain and collect DNA samples from large colorectal cancer kindreds, 2) test each kindred for linkage to candidate regions for colorectal cancer susceptibility loci, 3) perform a genomic search for colorectal cancer susceptibility loci, 4) create a fine structure map around the susceptibility loci identified, and 5) characterize the abnormal phenotype in carriers of the inherited susceptibility. The unique characteristics of the Utah population for genetic analysis will be an essential asset. We currently have the most informative set of breast cancer kindreds (in terms of LOD score) in the genetic epidemiology community. We also have the most informative set of melanoma susceptibility kindreds, which identified the 9p melanoma susceptibility locus (Cannon-Albright et al., 1992). We will ascertain large Utah kindreds likely to carry colorectal cancer susceptibility loci, and study those kindreds which are not linked to the chromosome 2 or chromosome 5 loci previously identified. These Utah kindreds will be pooled with unmapped kindreds available from our Johns Hopkins University (JHU) collaborators. All kindreds will be analyzed for linkage first with candidate loci and known genes (APC, chromosome 2 HNPCC, p53, DCC and ras). Then, in a genomic linkage search, they will be screened with a series of short tandem repeat markers (STRs). When a new colorectal cancer susceptibility locus is identified, we will identify key recombinants in these large kindreds and use them to create fine structure map around the susceptibility locus. New STR markers will be developed to aid in this effort. Haplotypes will be constructed around a susceptibility locus to identify gene carriers. We will characterize the phenotypic effect of each identified colorectal cancer susceptibility locus. This proposal is one of three submitted by an interdisciplinary collaborative group of investigators committed to understanding the etiology of colorectal cancer through genetic epidemiologic approaches. Our proposals are best described by the unifying theme, "Beyond identification of colon cancer genes." The other two proposals will examine the genetic epidemiology of the hereditary colorectal cancers (G. Petersen, P.I.). and diet and genetic alterations in colorectal neoplasia (S. Hamilton, P.I.). Genetic epidemiology provides a framework to study these questions in families and populations, and to develop new methodologies for analyzing these data.